Proprotein convertase 5/6 is critical for embryo implantation in women: Regulating receptivity by cleaving EBP50, modulating ezrin binding, and membrane-cytoskeletal interactions

Sophea Heng, Ana Cervero, Carlos Simon, Andrew N. Stephens, Ying Li, Jin Zhang, Sarah Paule, Adam Rainczuk, Harmeet Singh, Alicia Quinonero, Alejandro Tapia, Luis Velasquez, Lois Salamonsen, Luk J.F. Rombauts, Guiying Nie

Resultado de la investigación: Article

22 Citas (Scopus)

Resumen

Establishment of endometrial receptivity is vital for successful embryo implantation; its failure causes infertility. Epithelial receptivity acquisition involves dramatic structural changes in the plasma membrane and cytoskeleton. Proprotein convertase 5/6 (PC6), a serine protease of the proprotein convertase (PC) family, is up-regulated in the human endometrium specifically at the time of epithelial receptivity and stromal cell decidualization. PC6 is the only PCmembertightly regulated in this manner. The current study addressed the importance and mechanisms of PC6 action in regulating receptivity in women. PC6 was dysregulated in the endometrial epithelium during the window of implantation in infertile women of three demographically different cohorts. Its critical role in receptivity was evidenced by a significant reduction in mouse blastocyst attachment of endometrial epithelial cells after PC6 knockdown by small interfering RNA. Using a proteomic approach, we discovered that PC6 cleaved the key scaffolding protein, ezrin-radixin-moesin binding phosphoprotein 50 (EBP50), thereby profoundly affecting its interaction with binding protein ezrin (a key protein bridging actin filaments and plasma membrane), EBP50/ezrin cellular localization, and cytoskeleton-membrane connections. We further validated this novel PC6 regulation of receptivity in human endometrium in vivo in fertile vs. infertile patients. These results strongly indicate that PC6 plays a key role in regulating fundamental cellular remodeling processes, such as plasma membrane transformation and membrane-cytoskeletal interface reorganization. PC6 cleavage of a crucial scaffolding protein EBP50, thereby profoundly regulating membrane-cytoskeletal reorganization, greatly extends the current knowledge of PC biology and provides substantial new mechanistic insight into the fields of reproduction, basic cellular biology, and PC biochemistry.

Idioma originalEnglish
Páginas (desde-hasta)5041-5052
Número de páginas12
PublicaciónEndocrinology
Volumen152
N.º12
DOI
EstadoPublished - 1 dic 2011

Huella dactilar

Proprotein Convertase 5
Phosphoproteins
Membranes
Proprotein Convertases
Cell Membrane
Endometrium
Cytoskeleton
Epithelial Cells
moesin
ezrin
radixin
Proteins
Serine Proteases
Blastocyst
Stromal Cells
Actin Cytoskeleton
Biochemistry
Proteomics
Infertility
Small Interfering RNA

ASJC Scopus subject areas

  • Endocrinology

Citar esto

Heng, Sophea ; Cervero, Ana ; Simon, Carlos ; Stephens, Andrew N. ; Li, Ying ; Zhang, Jin ; Paule, Sarah ; Rainczuk, Adam ; Singh, Harmeet ; Quinonero, Alicia ; Tapia, Alejandro ; Velasquez, Luis ; Salamonsen, Lois ; Rombauts, Luk J.F. ; Nie, Guiying. / Proprotein convertase 5/6 is critical for embryo implantation in women : Regulating receptivity by cleaving EBP50, modulating ezrin binding, and membrane-cytoskeletal interactions. En: Endocrinology. 2011 ; Vol. 152, N.º 12. pp. 5041-5052.
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title = "Proprotein convertase 5/6 is critical for embryo implantation in women: Regulating receptivity by cleaving EBP50, modulating ezrin binding, and membrane-cytoskeletal interactions",
abstract = "Establishment of endometrial receptivity is vital for successful embryo implantation; its failure causes infertility. Epithelial receptivity acquisition involves dramatic structural changes in the plasma membrane and cytoskeleton. Proprotein convertase 5/6 (PC6), a serine protease of the proprotein convertase (PC) family, is up-regulated in the human endometrium specifically at the time of epithelial receptivity and stromal cell decidualization. PC6 is the only PCmembertightly regulated in this manner. The current study addressed the importance and mechanisms of PC6 action in regulating receptivity in women. PC6 was dysregulated in the endometrial epithelium during the window of implantation in infertile women of three demographically different cohorts. Its critical role in receptivity was evidenced by a significant reduction in mouse blastocyst attachment of endometrial epithelial cells after PC6 knockdown by small interfering RNA. Using a proteomic approach, we discovered that PC6 cleaved the key scaffolding protein, ezrin-radixin-moesin binding phosphoprotein 50 (EBP50), thereby profoundly affecting its interaction with binding protein ezrin (a key protein bridging actin filaments and plasma membrane), EBP50/ezrin cellular localization, and cytoskeleton-membrane connections. We further validated this novel PC6 regulation of receptivity in human endometrium in vivo in fertile vs. infertile patients. These results strongly indicate that PC6 plays a key role in regulating fundamental cellular remodeling processes, such as plasma membrane transformation and membrane-cytoskeletal interface reorganization. PC6 cleavage of a crucial scaffolding protein EBP50, thereby profoundly regulating membrane-cytoskeletal reorganization, greatly extends the current knowledge of PC biology and provides substantial new mechanistic insight into the fields of reproduction, basic cellular biology, and PC biochemistry.",
author = "Sophea Heng and Ana Cervero and Carlos Simon and Stephens, {Andrew N.} and Ying Li and Jin Zhang and Sarah Paule and Adam Rainczuk and Harmeet Singh and Alicia Quinonero and Alejandro Tapia and Luis Velasquez and Lois Salamonsen and Rombauts, {Luk J.F.} and Guiying Nie",
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Heng, S, Cervero, A, Simon, C, Stephens, AN, Li, Y, Zhang, J, Paule, S, Rainczuk, A, Singh, H, Quinonero, A, Tapia, A, Velasquez, L, Salamonsen, L, Rombauts, LJF & Nie, G 2011, 'Proprotein convertase 5/6 is critical for embryo implantation in women: Regulating receptivity by cleaving EBP50, modulating ezrin binding, and membrane-cytoskeletal interactions', Endocrinology, vol. 152, n.º 12, pp. 5041-5052. https://doi.org/10.1210/en.2011-1273

Proprotein convertase 5/6 is critical for embryo implantation in women : Regulating receptivity by cleaving EBP50, modulating ezrin binding, and membrane-cytoskeletal interactions. / Heng, Sophea; Cervero, Ana; Simon, Carlos; Stephens, Andrew N.; Li, Ying; Zhang, Jin; Paule, Sarah; Rainczuk, Adam; Singh, Harmeet; Quinonero, Alicia; Tapia, Alejandro; Velasquez, Luis; Salamonsen, Lois; Rombauts, Luk J.F.; Nie, Guiying.

En: Endocrinology, Vol. 152, N.º 12, 01.12.2011, p. 5041-5052.

Resultado de la investigación: Article

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T2 - Regulating receptivity by cleaving EBP50, modulating ezrin binding, and membrane-cytoskeletal interactions

AU - Heng, Sophea

AU - Cervero, Ana

AU - Simon, Carlos

AU - Stephens, Andrew N.

AU - Li, Ying

AU - Zhang, Jin

AU - Paule, Sarah

AU - Rainczuk, Adam

AU - Singh, Harmeet

AU - Quinonero, Alicia

AU - Tapia, Alejandro

AU - Velasquez, Luis

AU - Salamonsen, Lois

AU - Rombauts, Luk J.F.

AU - Nie, Guiying

PY - 2011/12/1

Y1 - 2011/12/1

N2 - Establishment of endometrial receptivity is vital for successful embryo implantation; its failure causes infertility. Epithelial receptivity acquisition involves dramatic structural changes in the plasma membrane and cytoskeleton. Proprotein convertase 5/6 (PC6), a serine protease of the proprotein convertase (PC) family, is up-regulated in the human endometrium specifically at the time of epithelial receptivity and stromal cell decidualization. PC6 is the only PCmembertightly regulated in this manner. The current study addressed the importance and mechanisms of PC6 action in regulating receptivity in women. PC6 was dysregulated in the endometrial epithelium during the window of implantation in infertile women of three demographically different cohorts. Its critical role in receptivity was evidenced by a significant reduction in mouse blastocyst attachment of endometrial epithelial cells after PC6 knockdown by small interfering RNA. Using a proteomic approach, we discovered that PC6 cleaved the key scaffolding protein, ezrin-radixin-moesin binding phosphoprotein 50 (EBP50), thereby profoundly affecting its interaction with binding protein ezrin (a key protein bridging actin filaments and plasma membrane), EBP50/ezrin cellular localization, and cytoskeleton-membrane connections. We further validated this novel PC6 regulation of receptivity in human endometrium in vivo in fertile vs. infertile patients. These results strongly indicate that PC6 plays a key role in regulating fundamental cellular remodeling processes, such as plasma membrane transformation and membrane-cytoskeletal interface reorganization. PC6 cleavage of a crucial scaffolding protein EBP50, thereby profoundly regulating membrane-cytoskeletal reorganization, greatly extends the current knowledge of PC biology and provides substantial new mechanistic insight into the fields of reproduction, basic cellular biology, and PC biochemistry.

AB - Establishment of endometrial receptivity is vital for successful embryo implantation; its failure causes infertility. Epithelial receptivity acquisition involves dramatic structural changes in the plasma membrane and cytoskeleton. Proprotein convertase 5/6 (PC6), a serine protease of the proprotein convertase (PC) family, is up-regulated in the human endometrium specifically at the time of epithelial receptivity and stromal cell decidualization. PC6 is the only PCmembertightly regulated in this manner. The current study addressed the importance and mechanisms of PC6 action in regulating receptivity in women. PC6 was dysregulated in the endometrial epithelium during the window of implantation in infertile women of three demographically different cohorts. Its critical role in receptivity was evidenced by a significant reduction in mouse blastocyst attachment of endometrial epithelial cells after PC6 knockdown by small interfering RNA. Using a proteomic approach, we discovered that PC6 cleaved the key scaffolding protein, ezrin-radixin-moesin binding phosphoprotein 50 (EBP50), thereby profoundly affecting its interaction with binding protein ezrin (a key protein bridging actin filaments and plasma membrane), EBP50/ezrin cellular localization, and cytoskeleton-membrane connections. We further validated this novel PC6 regulation of receptivity in human endometrium in vivo in fertile vs. infertile patients. These results strongly indicate that PC6 plays a key role in regulating fundamental cellular remodeling processes, such as plasma membrane transformation and membrane-cytoskeletal interface reorganization. PC6 cleavage of a crucial scaffolding protein EBP50, thereby profoundly regulating membrane-cytoskeletal reorganization, greatly extends the current knowledge of PC biology and provides substantial new mechanistic insight into the fields of reproduction, basic cellular biology, and PC biochemistry.

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